U.S. patent application number 13/810741 was filed with the patent office on 2013-05-09 for process for preparing pyrano - [2,3-c]pyridine derivitaves.
The applicant listed for this patent is Douglas Mans, Joseph Sisko, Hao Yin. Invention is credited to Douglas Mans, Joseph Sisko, Hao Yin.
Application Number | 20130116436 13/810741 |
Document ID | / |
Family ID | 45497409 |
Filed Date | 2013-05-09 |
United States Patent
Application |
20130116436 |
Kind Code |
A1 |
Sisko; Joseph ; et
al. |
May 9, 2013 |
PROCESS FOR PREPARING PYRANO - [2,3-C]PYRIDINE DERIVITAVES
Abstract
The present invention relates to a process comprising the step
of dehydrating a compound of Formula (I): ##STR00001## with a
suitable dehydrating reagent to form a compound of Formula (II):
##STR00002## wherein R.sup.1-R.sup.7are as defined herein.
Compounds of Formula (II) have shown promise as intermediates to
compounds useful for treating bacterial infections.
Inventors: |
Sisko; Joseph; (King of
Prussia, PA) ; Mans; Douglas; (King of Prussia,
PA) ; Yin; Hao; (King of Prussia, PA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Sisko; Joseph
Mans; Douglas
Yin; Hao |
King of Prussia
King of Prussia
King of Prussia |
PA
PA
PA |
US
US
US |
|
|
Family ID: |
45497409 |
Appl. No.: |
13/810741 |
Filed: |
July 19, 2011 |
PCT Filed: |
July 19, 2011 |
PCT NO: |
PCT/US11/44489 |
371 Date: |
January 17, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61365880 |
Jul 20, 2010 |
|
|
|
Current U.S.
Class: |
546/115 |
Current CPC
Class: |
C07D 491/044 20130101;
C07D 491/052 20130101; A61P 31/00 20180101 |
Class at
Publication: |
546/115 |
International
Class: |
C07D 491/052 20060101
C07D491/052 |
Claims
1. A process comprising the step of dehydrating a compound of
Formula (I): ##STR00038## with a suitable dehydrating reagent to
form a compound of Formula (II): ##STR00039## wherein R.sup.1 is
--CH.dbd.CH--R.sup.8 or --CH.sub.2--CH.dbd.CH--R.sup.9; R.sup.2 is
C.sub.1-C.sub.4-alkyl; R.sup.3 is H, C.sub.1-C.sub.4-alkyl, benzyl,
-phenyl-(R.sup.10).sub.x, or
--C.sub.1-C.sub.4-alkyl-COO--C.sub.1-C.sub.4-alkyl; each R.sup.4 is
independently H, or C.sub.1-C.sub.4-alkyl; each R.sup.5 and each
R.sup.6 are independently H, C.sub.1-C.sub.4-alkyl,
--O--C.sub.1-C.sub.4-alkyl, or --S--C.sub.1-C.sub.4-alkyl; R.sup.7
is R.sup.8 or --CH.sub.2--R.sup.9; R.sup.8 is H,
C.sub.1-C.sub.4-alkyl, -phenyl-(R.sup.10).sub.x, or
--COO--C.sub.1-C.sub.4-alkyl; R.sup.9 is H, C.sub.1-C.sub.3-alkyl,
-phenyl-(R.sup.10).sub.x, or --COO--C.sub.1-C.sub.4-alkyl; each
R.sup.10 is independently halo, C.sub.1-C.sub.6-alkyl,
--O--C.sub.1-C.sub.4-alkyl, or --S--C.sub.1-C.sub.4-alkyl; and each
x is independently 0, 1, or 2.
2. The process of claim 1 which is further carried out in the
presence of an organic base, wherein the dehydrating reagent is
Tf.sub.2O or P.sub.2O.sub.5; and R.sup.4, R.sup.5, and R.sup.6 are
each independently H or C.sub.1-C.sub.4-alkyl.
3. The process of claim 2 wherein R.sup.4, R.sup.5, and R.sup.6 are
each independently H or methyl; and the organic base is pyridine,
triethylamine, or diisopropylethylamine.
4. The process of claim 3 wherein each of R.sup.4, R.sup.5, and
R.sup.6 is H; the dehydrating reagent is Tf.sub.2O; and the organic
base is used in an amount of at least 1 equivalent with respect to
the compound of Formula (I) and less than the amount of the
dehydrating reagent, in equivalents.
5. The process of claim 1 which further comprises the steps of: a)
reducing the compound of Formula (II) with a suitable reducing
reagent to form a compound of Formula (III): ##STR00040## and b)
oxidizing the compound of Formula (III) with a suitable oxidizing
reagent to form a compound of Formula (IV): ##STR00041##
6. The process of claim 1 which further comprises the step of
reducing the compound of Formula (II) with a suitable reducing
reagent to form a compound of Formula (IV): ##STR00042##
7. The process of claim 1 comprising the step of dehydrating a
compound of Formula (V): ##STR00043## with a suitable dehydrating
reagent to form a compound of Formula (VI): ##STR00044## wherein
R.sup.2 is C.sub.1-C.sub.4-alkyl.
8. The process of claim 7 wherein the dehydrating reagent is
Tf.sub.2O or P.sub.2O.sub.5.
9. The process of claim 7 wherein the dehydrating reagent is
Tf.sub.2O; and R.sup.2 is methyl or ethyl.
10. The process of claim 7 wherein the process is carried out in
the presence of an organic base in an amount of at least 1
equivalent with respect to the compound of Formula (V) and less
than the amount of the dehydrating reagent, in equivalents.
11. The process of claim 7 which further comprises the steps of: a)
reducing the compound of Formula (VI) with a suitable reducing
reagent to form a compound of Formula (VII): ##STR00045## and b)
oxidizing the compound of Formula (VII) with a suitable oxidizing
reagent to form a compound of Formula (VIII): ##STR00046##
12. The process of claim 7 which further comprises the step of
reducing the compound of Formula (VI) with a suitable reducing
reagent to form a compound of Formula (VIII): ##STR00047##
13. The process of claim 5 wherein the reducing reagent is
diisobutylaluminium hydride, LiAlH.sub.4, LiBH.sub.4, or
NaBH.sub.4.
14.-17. (canceled)
18. The process of claim 11 wherein the reducing agent is
diisobutylaluminium hydride, LiAlH.sub.4, LiBH.sub.4, or
NaBH.sub.4.
19. The process of claim 13 wherein the reducing reagent is
LiBH.sub.4.
20. The process of claim 18 wherein the reducing reagent is
LiBH.sub.4.
21. The process of claim 5 wherein the oxidizing reagent is
MnO.sub.2, Swern oxidation reagents, 2-iodoxybenzoic acid, pyridine
sulphur trioxide, or Dess-Martin periodinane.
22. The process of claim 11 wherein the oxidizing reagent is
MnO.sub.2, Swern oxidation reagents, 2-iodoxybenzoic acid, pyridine
sulphur trioxide, or Dess-Martin periodinane.
23. The process of claim 21 wherein the oxidizing reagent is
pyridine sulphur trioxide.
24. The process of claim 22 wherein the oxidizing reagent is
pyridine sulphur trioxide.
25. The process of claim 6 wherein the reducing reagent is
diisobutylaluminium hydride.
26. The process of claim 12 wherein the reducing reagent is
diisobutylaluminium hydride.
Description
BACKGROUND OF THE INVENTION
[0001] The present invention relates to pyrano-[2,3-c]pyridine
derivatives and methods for their preparation.
3,4-Dihydro-2H-pyrano[2,3-c]pyridine-6-carbaldehyde, disclosed in
WO2004058144, is characterized by the following Formula (VIII):
##STR00003##
[0002] Pyrano-[2,3-c]pyridine derivatives have shown promise as
useful intermediates to compounds useful for treating bacterial
infections. Previously disclosed methods for preparing
pyrano-[2,3-c]pyridine-6-carbaldehyde are arduous, requiring many
steps using expensive starting materials and resulting in
unsatisfactory overall yields. (See WO2003042210, Example 18;
WO2004058144, Example 126(a)-(e)) It would therefore be
advantageous to discover alternative ways of preparing this
building block from relatively inexpensive chemicals.
SUMMARY OF THE INVENTION
[0003] In one aspect, the present invention is a process comprising
dehydrating a compound of Formula (I):
##STR00004##
with a suitable dehydrating reagent to form a compound of Formula
(II):
##STR00005## [0004] wherein R.sup.1 is --CH.dbd.CH--R.sup.8 or
--CH.sub.2--CH.dbd.CH--R.sup.9; [0005] R.sup.2 is
C.sub.1-C.sub.4-alkyl; [0006] R.sup.3 is H, C.sub.1-C.sub.4-alkyl,
benzyl, -phenyl-(R.sup.10).sub.x, or
--C.sub.1-C.sub.4-alkyl-COO--C.sub.1-C.sub.4-alkyl; [0007] each
R.sup.4 is independently H, or C.sub.1-C.sub.4-alkyl; [0008] each
R.sup.5 and each R.sup.6 are independently H,
C.sub.1-C.sub.4-alkyl, --O--C.sub.1-C.sub.4-alkyl, or
--S--C.sub.1-C.sub.4-alkyl; [0009] R.sup.7 is R.sup.8 or
--CH.sub.2--R.sup.9; [0010] R.sup.8 is H, C.sub.1-C.sub.4-alkyl,
-phenyl-(R.sup.10).sub.x, or --COO--C.sub.1-C.sub.4-alkyl; [0011]
R.sup.9 is H, C.sub.1-C.sub.3-alkyl, -phenyl-(R.sup.10).sub.x, or
--COO--C.sub.1-C.sub.4-alkyl; [0012] each R.sup.10 is independently
halo, C.sub.1-C.sub.4-alkyl, --O--C.sub.1-C.sub.6-alkyl, or
--S--C.sub.1-C.sub.4-alkyl; and [0013] each x is independently 0,
1, or 2.
[0014] In another aspect, the present invention is a process
comprising the step of dehydrating a compound of Formula (V):
##STR00006##
with a suitable dehydrating reagent to form a compound of Formula
(VI):
##STR00007##
wherein R.sup.2 is C.sub.1-C.sub.4-alkyl. Compounds of Formula (II)
have shown promise as intermediates to compounds useful for
treating bacterial infections.
DETAILED DESCRIPTION OF THE INVENTION
[0015] In a first aspect, the present invention is a process
comprising dehydrating a compound of Formula (I):
##STR00008##
with a suitable dehydrating reagent to form a compound of Formula
(II):
##STR00009##
wherein R.sup.1-R.sup.7 are as previously defined.
[0016] C.sub.1-C.sub.4-alkyl is used herein to refer to a straight
chain or branched alkyl group with up to four carbon atoms.
Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl,
sec-butyl, and t-butyl.
[0017] Similarly, C.sub.1-C.sub.3-alkyl refers to methyl, ethyl,
n-propyl, or isopropyl.
[0018] In another embodiment, R.sup.4, R.sup.5, and R.sup.6 are
each independently H or C.sub.1-C.sub.4-alkyl.
[0019] In another embodiment, R.sup.4, R.sup.5, and R.sup.6 are
each independently H or methyl.
[0020] In another embodiment, each of R.sup.4, R.sup.5, and R.sup.6
is H.
[0021] Examples of suitable dehydrating reagents include
trifluoromethanesulfonic anhydride (Tf.sub.2O) and phosphorus
pentoxide (P.sub.2O.sub.5), preferably Tf.sub.2O. The reaction of
Compound (I) to Compound (II) [or Compound (V) to Compound (VI)] is
advantageously carried out in the presence of a suitable base,
preferably an organic base such as pyridine, triethylamine, or
diisopropylethylamine Preferably, the base is used in a range of
from 1 equivalent with respect to Compound (I) to less than the
amount, in equivalents, of the dehydrating reagent.
[0022] A compound of Formula (Ia):
##STR00010##
can be prepared, for example, by reaction of
Cl--CO--CO.sub.2--R.sup.2 with a compound of Formula (4):
##STR00011##
in the presence of a suitable base, preferably an organic base,
where R.sup.8 is as previously defined.
[0023] The compound of Formula (4) can be prepared by deprotecting
a compound of Formula (3):
##STR00012##
under suitable deprotecting conditions, preferably by reaction with
a strong acid, such as HCl, H.sub.2SO.sub.4, MsOH or TsOH.
[0024] The compound of Formula (3) can be prepared by condensing a
compound of Formula (1):
##STR00013##
with a compound of Formula (2):
##STR00014##
under suitable condensation conditions, for example, in the
presence of 1,1'-carbonyldiimidazole.
[0025] A compound of Formula (Ib):
##STR00015##
can be prepared in a similar manner to the compound of Formula
(Ia), where R.sup.9 is as previously defined.
[0026] The compound of Formula (II):
##STR00016##
can be contacted with a suitable reducing reagent to form a
compound of Formula (III):
##STR00017##
[0027] Examples of suitable reducing reagents include
diisobutylaluminium hydride, LiAlH.sub.4, LiBH.sub.4, and
NaBH.sub.4.
[0028] The compound of Formula (III) can be contacted with a
suitable oxidizing reagent to form a compound of Formula (IV):
##STR00018##
[0029] Examples of suitable oxidizing reagents include MnO.sub.2,
Swern oxidation reagents, 2-iodoxybenzoic acid, pyridine sulphur
trioxide, and Dess-Martin periodinane. Alternatively, the compound
of Formula (IV):
##STR00019##
can be prepared by reducing the compound of Formula (II):
##STR00020##
with a suitable reducing reagent, such as diisobutylaluminium
hydride.
Schemes
[0030] Scheme 1 illustrates one aspect of the present invention.
Compound (3) can be prepared by contacting acid (1) with alcohol
(2) under suitable condensation conditions, for example, in the
presence of 1,1'-carbonyldiimidazole. The protecting group is
removed from compound (3) to form amine (4) under suitable
deprotecting conditions, preferably by reaction with a strong acid,
such as HCl, H.sub.2SO.sub.4, MsOH or TsOH.
[0031] The compound of Formula (Ia) can be prepared by contacting
amine (4) with X--CO--CO.sub.2--R.sup.2 (X=halo or --OCH.sub.3) in
the presence of a suitable base, preferably, an organic base such
as triethylamine.
[0032] The compound of Formula (IIa) can be prepared by treatment
of the compound of Formula (Ia) with suitable base and dehydrating
reagent, for example, pyridine and Tf.sub.2O.
[0033] The compound of Formula (IVa) can be prepared in at least
two ways. For example, the compound of Formula (IIa) can be reduced
to alcohol (IIIa) using a suitable reducing reagent such as
diisobutylaluminium hydride, LiAlH.sub.4, LiBH.sub.4, or
NaBH.sub.4. Alcohol (IIIa) can then be oxidized to form the
compound of Formula (IVa) using a suitable oxidizing reagent such
as MnO.sub.2, Swern oxidation reagents, 2-iodoxybenzoic acid,
pyridine sulphur trioxide, or Dess-Martin periodinane.
[0034] Alternatively, the compound of Formula (IIa) can be reduced
to form the compound of Formula (IVa) using a suitable reducing
reagent such as diisobutylaluminium hydride.
##STR00021##
[0035] Another embodiment of the present invention is illustrated
in Scheme 2. The compound of Formula (IVb) can be prepared in a
similar manner as the compounds in Scheme 1 starting from alcohol
(6).
##STR00022##
EXAMPLES
[0036] The following examples are illustrative of the process of
the present invention and are not intended to limit the scope of
the invention.
Example 1
Methyl 3,4-dihydro-2H-pyrano[2,3-c]pyridine-6-carboxylate
##STR00023##
[0037] (a) Methyl
2-oxo-2-((2-oxo-2-(pent-4-en-1-yloxy)ethyl)amino)acetate
##STR00024##
[0039] To a 1-L reactor was charged 1,1'-carbonyldiimidazole (CDI)
(44.0 g, 0.95 eq) and tert-butyl methyl ether (TBME) (150 mL). The
mixture was heated with stirring to .about.40.degree. C. whereupon
a solution of N-Boc-glycine (50 g, 1 eq) in TBME (200 mL) was added
and stirring continued for 0.5 h. Pent-4-en-1-ol (23 g, 0.95 eq)
was then added over 30 min and stirring was continued at 40.degree.
C. for 2 h then cooled to 20.degree. C. 1N HCl (125 mL) was added
to form a biphasic mixture. The layers were separated and the
organic layer was washed with 1N HCl (1.times.125 mL) followed by
water (1.times.125 mL). The TBME was distilled off and the crude
pent-4-en-1-yl2-((tert-butoxycarbonyl)amino)acetate was then
azeotropically dried with toluene (200 mL). The mixture was heated
to 40.degree. C. and sufficient toluene was added to bring the
total volume of toluene to .about.200 mL. Methanesulfonic acid (34
g, 1.25 eq) was added and the mixture was stirred at 40.degree. C.
for 2 h then cooled to 20.degree. C. The mixture was then
transferred into a vessel containing dimethyl oxalate (34 g, 1 eq)
and the temperature of the vessel was maintained at 20.degree. C.
with stirring. Triethylamine (43 g, 1.5 eq) was then added to this
mixture stirring was continued for a further 1 h. The mixture was
washed with water (125 mL). The toluene solution was concentrated
with azeotropic drying to give methyl
2-oxo-2-((2-oxo-2-(pent-4-en-1-yloxy)ethyl)amino)acetate as an oil.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 7.55 (s, 1H),
5.73-5.86 (m, 1H), 4.97-5.10 (m, 2H), 4.21 (t, J=6.65 Hz, 2H), 4.13
(d, J=5.52 Hz, 2H), 3.93 (s, 3H), 2.13 (q, J=7.42 Hz, 2H),
1.71-1.85 (m, 2H); .sup.13C NMR (75 MHz, CDCl.sub.3) .delta. ppm
168.58, 160.35, 156.29, 137.05, 115.56, 65.25, 53.72, 41.48, 29.84,
27.56; HRMS (M+Na) m/z, calcd for C.sub.10H.sub.15NO.sub.5Na,
252.0848; found, 252.0852.
(b) The Title Compound
[0040] Methyl
2-oxo-2-((2-oxo-2-(pent-4-en-1-yloxy)ethyl)amino)acetate (42.5 g, 1
eq) and dichloromethane (DCM) (425 mL) were added to a vessel with
stirring followed by the addition of pyridine (17.6 g, 1.2 eq).
Tf.sub.2O (78.5 g, 1.5 eq) was added over 45 min to the mixture
maintaining an internal temperature of .about.25.degree. C. The
mixture was stirred for 6 h at which point the reaction was
carefully quenched by the addition of 20 wt % aqueous NaOAc (255
mL) to form a biphasic solution. The aqueous layer was extracted
with DCM (85 mL). The combined organic layers were washed first
with water (127.5 mL) and 10 wt % citric acid solution (170 mL). 6N
HCl (127.5 mL) was added to the mixture to form a biphasic mixture.
The two layers were separated and the organic layer was extracted
with 6 N HCl (85 mL). The acidic aqueous layers were combined and
DCM (127.5 mL) was added. While maintaining the temperature below
25.degree. C., 28 wt % aqueous NH.sub.4OH was slowly added until
the pH of the aqueous layer reached 3-5. The two layers were
separated and the aqueous layer was extracted with DCM (85 mL). The
combined organic layers were washed with water (85 mL). The organic
solution was concentrated under reduced pressure to provide the
title compound as an oil which solidified on standing. .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. ppm 8.17 (s, 1H), 7.80-7.86 (m, 1H),
4.26 (t, J=5.19 Hz, 2H), 3.92 (s, 3H), 2.79 (t, J=6.44 Hz, 2H),
1.97-2.09 (m, 2H); .sup.13C NMR (75 MHz, CDCl.sub.3) .delta. ppm
165.11, 154.25, 138.95, 138.64, 130.06, 126.13, 65.55, 51.99,
23.57, 20.67; HRMS (M+Na) m/z, calcd for
C.sub.10H.sub.11NO.sub.3Na, 216.0637; found, 216.0643.
Example 2
Ethyl
8-methyl-3,4-dihydro-2H-pyrano[2,3-c]pyridine-6-carboxylate
##STR00025##
[0041] (a) Pent-4-en-1-yl 2-(2-ethoxy-2-oxoacetamido)propanoate
##STR00026##
[0043] N-(t-Butoxycarbonyl)alanine (3.1 g, 1 eq) and DCM (50 mL)
were added to a vessel with stirring followed by the addition of
CDI (3.1 g, 1.15 eq). The mixture was stirred at ambient
temperature for 18 h after which time 4-penten-1-ol (1.8 g, 1.25
eq) was added. The mixture was stirred a further 18 h at ambient
temperature at which point the reaction was quenched with 1N HCl. A
biphasic mixture was formed and the layers were separated. The
organic layer was washed with saturated aqueous NaHCO.sub.3
solution and then concentrated to give
pent-4-en-1-yl2-((tert-butoxycarbonyl)amino)propanoate as an oil.
The oil was dissolved in DCM (50 mL) and methanesulfonic acid (2.2
g, 1.4 eq) was added. The mixture was stirred at ambient
temperature for .about.22 h then cooled in an ice/water bath. Ethyl
2-chloro-2-oxoacetate (3.4 g, 1.5 eq) was added followed by
drop-wise addition of triethylamine (5.0 g, 3 eq). The mixture was
stirred for 7 h after which time the reaction was quenched by 1N
HCl to form a biphasic mixture. The layers were separated and the
organic layer was washed with a saturated aqueous NaHCO.sub.3
solution. The organic layer was then concentrated under reduced
pressure to provide pent-4-en-1-yl
2-(2-ethoxy-2-oxoacetamido)propanoate as a yellow oil. .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. ppm 7.64 (d, J=6.94 Hz, 1H),
5.66-5.83 (m, 1H), 4.90-5.05 (m, 2H), 4.49-4.62 (m, 1H), 4.31 (qd,
J=7.17, 2.26 Hz, 2H), 4.13 (td, J=6.59, 2.13 Hz, 2H), 2.02-2.14 (m,
2H), 1.67-1.78 (m, 2H), 1.44 (d, J=7.19 Hz, 3H), 1.34 (t, J=7.15
Hz, 3H); .sup.13C NMR (75 MHz, CDCl.sub.3) .delta. ppm 171.64,
159.94, 155.83, 136.94, 115.40, 64.98, 63.10, 48.40, 29.71, 27.44,
17.88, 13.80; HRMS (M+Na) m/z, calcd for
C.sub.12H.sub.19NO.sub.5Na, 280.1161; found, 280.1166.
(b) The Title Compound
[0044] Pent-4-en-1-yl2-(2-ethoxy-2-oxoacetamido)propanoate (1.05 g,
1 eq) and DCM (15 mL) were added to a vessel with stirring.
Pyridine (0.39 g, 1.2 eq) was then added and the mixture was cooled
to 15.degree. C. Tf.sub.2O (1.7 g, 1.5 eq) was added to the mixture
over 15 min and the mixture was warmed to ambient temperature to
stir for 1.5 h. The reaction was quenched by the addition of DCM
and 20 wt % aqueous NaOAc to form a biphasic mixture. The layers
were separated and the organic layer was washed with water. The
organic layer was then concentrated under reduced pressure to
provide the title compound as yellow solid. .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. ppm 7.62 (s, 1H), 4.32 (q, J=7.12 Hz, 2H),
4.16-4.25 (m, 2H), 2.70 (t, J=6.44 Hz, 2H), 2.37 (s, 3H), 1.86-2.03
(m, 2H), 1.31 (t, J=7.12 Hz, 3H); .sup.13C NMR (75 MHz, CDCl.sub.3)
.delta. ppm 165.15, 152.44, 147.98, 137.72, 128.73, 124.80, 66.85,
61.09, 23.98, 21.06, 18.98, 14.11; HRMS (M+H) m/z, calcd for
C.sub.12H.sub.16NO.sub.3, 222.1130; found, 222.1133.
Example 3
Ethyl
8-benzyl-3,4-dihydro-2H-pyrano[2,3-c]pyridine-6-carboxylate
##STR00027##
[0045] (a) Pent-4-en-1-yl
2-(2-ethoxy-2-oxoacetamido)-3-phenylpropanoate
##STR00028##
[0047] Pent-4-en-1-yl2-(2-ethoxy-2-oxoacetamido)-3-phenylpropanoate
was prepared in a similar manner as Example 2(a) starting with
N-(t-butoxycarbonyl)phenylalanine (1.0 g). .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. ppm 7.52 (d, J=8.03 Hz, 1H), 7.28-7.37 (m, 3H),
7.15-7.19 (m, 2H), 5.73-5.84 (m, 1H), 5.06-5.10 (m, 1H), 5.01-5.05
(m, 1H), 4.87-4.95 (m, 1H), 4.38 (qd, J=7.15, 1.72 Hz, 2H),
4.11-4.21 (m, 2H), 3.21 (d, J=6.11 Hz, 2H), 2.05-2.13 (m, 2H),
1.69-1.79 (m, 2H), 1.41 (t, J=7.15 Hz, 3H); .sup.13C NMR (75 MHz,
CDCl.sub.3) .delta. ppm 170.30, 159.85, 155.93, 137.01, 135.14,
129.10, 128.62, 127.26, 115.43, 65.10, 63.22, 53.57, 37.70, 29.75,
27.42, 13.85; HRMS (M+H) m/z, calcd for C.sub.18H.sub.24NO.sub.5,
334.1654; found 334.1665.
(b) The Title Compound
[0048] Pent-4-en-1-yl2-(2-ethoxy-2-oxoacetamido)-3-phenylpropanoate
(0.80 g, 1 eq) and DCM (15 mL) were added to a vessel with
stirring. Pyridine (0.23 g, 1.2 eq) was then added and the mixture
was cooled to 15.degree. C. Tf.sub.2O (1.0 g, 1.5 eq) was added to
the mixture over 15 min and the mixture was warmed to ambient
temperature. The solution was stirred for 3.5 h after which time
the reaction was quenched by DCM and 20 wt % aqueous NaOAc to form
a biphasic mixture. The layers were separated and the organic layer
was extracted with 6N HCl (3.times.10 mL). The combined acid layers
were washed with DCM and the pH was adjusted to .about.9 with solid
K.sub.2CO.sub.3. The basic aqueous layer was extracted with DCM.
The organic layer was concentrated under reduced pressure to
provide the title compound. .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. ppm 7.74 (s, 1H), 7.10-7.35 (m, 5H), 4.43 (q, J=7.12 Hz,
2H), 4.22-4.29 (m, 2H), 4.21 (s, 2H), 2.78 (t, J=6.41 Hz, 2H),
1.93-2.06 (m, 2H), 1.41 (t, J=7.12 Hz, 3H); .sup.13C NMR (75 MHz,
CDCl.sub.3) .delta. ppm 165.08, 152.25, 149.62, 138.86, 138.06,
129.62, 128.61, 127.80, 125.61, 125.23, 66.70, 60.97, 38.55, 23.93,
20.92, 14.10; HRMS (M+H) m/z, calcd for C.sub.18H.sub.20NO.sub.3,
298.1443; found 298.1450.
Example 4
Ethyl
8-phenyl-3,4-dihydro-2H-pyrano[2,3-c]pyridine-6-carboxylate
##STR00029##
[0049] (a) Ethyl
2-oxo-2-((2-oxo-2-(pent-4-en-1-yloxy)-1-phenylethyl)amino)acetate
##STR00030##
[0051] Ethyl
2-oxo-2-((2-oxo-2-(pent-4-en-1-yloxy)-1-phenylethyl)amino)acetate
was prepared in a similar manner as Example 2(a) starting from
.alpha.-[[(1,1-dimethylethoxy)carbonyl]amino]-benzeneacetic acid
(0.96 g). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 8.01 (d,
J=7.11 Hz, 1H), 7.32-7.43 (m, 5H), 5.63-5.78 (m, 1H), 5.58 (d,
J=7.61 Hz, 1H), 4.88-4.98 (m, 2H), 4.36 (q, J=7.11 Hz, 2H),
4.11-4.24 (m, 2H), 1.93-2.04 (m, 2H), 1.70 (qd, J=7.12, 6.88, 2.05
Hz, 2H), 1.39 (t, J=7.15 Hz, 3H); .sup.13C NMR (75 MHz, CDCl.sub.3)
.delta. ppm 169.75, 159.93, 155.72, 136.94, 135.47, 129.02, 128.83,
127.26, 115.53, 65.40, 63.32, 56.69, 29.63, 27.44, 13.91; HRMS
(M+H) m/z, calcd for C.sub.17H.sub.22NO.sub.5, 320.1498; found
320.1512.
(b) The Title Compound
[0052] Ethyl
8-phenyl-3,4-dihydro-2H-pyrano[2,3-c]pyridine-6-carboxylate was
prepared in a similar manner as Example 3(b) starting from ethyl
2-oxo-2-((2-oxo-2-(pent-4-en-1-yloxy)-1-phenylethyl)amino)acetate
(0.91 g). .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. ppm 7.91-7.98
(m, 2H), 7.84 (s, 1H), 7.34-7.49 (m, 3H), 4.44 (q, J=7.12 Hz, 2H),
4.29-4.38 (m, 2H), 2.91 (t, J=6.44 Hz, 2H), 2.02-2.18 (m, 2H), 1.43
(t, J=7.12 Hz, 3H); .sup.13C NMR (75 MHz, CDCl.sub.3) .delta. ppm
165.11, 152.06, 149.30, 146.60, 138.65, 136.72, 135.82, 130.64,
129.30, 128.06, 127.59, 125.48, 66.89, 61.07, 24.37, 20.84, 14.09;
HRMS (M+H) m/z, calcd for C.sub.17H.sub.18NO.sub.3, 284.1287; found
284.1301.
Example 5
Methyl
5-methyl-3,4-dihydro-2H-pyrano[2,3-c]pyridine-6-carboxylate
##STR00031##
[0053] (a) (E)-Methyl
2-((2-(hex-4-en-1-yloxy)-2-oxoethyl)amino)-2-oxoacetate
##STR00032##
[0055] To a vessel maintained at 40.degree. C. was charged CDI
(2.75 g, 0.95 eq) and TBME (9 mL). To this mixture was added with
stirring a solution of N-(t-butoxycarbonyl)glycine (3.1 g, 1.0 eq)
dissolved in TBME (12 mL) over 30 min. Stirring was continued for
an additional 30 min, whereupon trans-4-hexen-1-ol (1.7 g, 0.95 eq)
was added over 30 min. The mixture was maintained with stirring at
40.degree. C. for an additional 3.5 h, then cooled to ambient
temperature and stirred a further 14 h. The mixture was washed with
1N HCl (2.times.7.8 mL) then water (1.times.7.8 mL). The organic
layer was dried over Na.sub.2SO.sub.4, filtered and concentrated to
give (E)-hex-4-en-1-yl2-((tert-butoxycarbonyl)amino)acetate as an
oil. The oil was dissolved in DCM (12 mL) and 4.0 M HCl in dioxane
(2.8 mL) was added drop-wise. The mixture was stirred at ambient
temperature for 1.5 h then the mixture was heated to 35.degree. C.
and stirred for 3 h. 4.0 M HCl in dioxane (2.8 mL) was added
drop-wise. After 6 h at 35.degree. C. a further dose of 4.0 M HCl
in dioxane (2.8 mL) was added drop-wise and the mixture was stirred
for a further 4 h. The mixture was cooled to ambient temperature
and the solvent was removed under reduced pressure. A portion of
the residue (1.0 g) was dissolved in DCM (8 mL) and methyl
2-chloro-2-oxoacetate (0.63 g) was added. Triethylamine (1.0 g) was
added drop-wise over 20 min. The mixture was stirred for 1 h before
being quenched by 1N HCl (2.5 mL) to form a biphasic mixture. The
layers were separated and the organic layer was washed with 1N HCl
(1.times.2.5 mL), water (1.times.2.5 mL) and concentrated under
reduced pressure to provide an oil. Flash column chromatography
(SiO.sub.2, 10.fwdarw.60% EtOAc/Hex gradient) provided the title
compound as an oil as a 95:5 mixture of trans:cis isomers. .sup.1H
NMR (300 MHz, CDCl.sub.3) .delta. ppm 7.57 (s, 1H), 5.31-5.55 (m,
2H), 4.17 (t, J=6.69 Hz, 2H), 4.12 (d, J=5.51 Hz, 2H), 3.92 (s,
3H), 1.97-2.10 (m, 2H), 1.67-1.77 (m, 2H), 1.62-1.67 (m, 3H);
.sup.13C NMR (75 MHz, CDCl.sub.3) .delta. ppm 168.60, 160.35,
156.28, 129.49, 126.12, 65.34, 53.68, 41.47, 28.62, 28.17, 17.84;
HRMS (M+H) m/z, calcd for C.sub.11H.sub.18NO.sub.5, 244.1185; found
244.1187.
(b) The Title Compound
[0056] (E)-Methyl
2-((2-(hex-4-en-1-yloxy)-2-oxoethyl)amino)-2-oxoacetate (0.24 g, 1
eq) and DCM (2.4 mL) were added to a vessel with stirring followed
by the addition of pyridine (95 mg, 1.2 eq). Tf.sub.2O (0.42 g, 1.5
eq) was then added over 45 min at ambient temperature and the
mixture was stirred at ambient temperature for 48 h. The mixture
was washed with 20 wt % aqueous NaOAc (2.times.1.5 mL), 10 wt %
aqueous citric acid (3.times.1.5 mL), and water (1.times.1.5 mL).
The organic layer was then concentrated under reduced pressure to
provide the title compound as a solid. .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. ppm 8.10 (s, 1H), 4.15-4.25 (m, 2H), 3.94 (s,
3H), 2.71 (t, J=6.56 Hz, 2H), 2.47 (s, 3H), 2.00-2.18 (m, 2H);
.sup.13C NMR (75 MHz, CDCl.sub.3) .delta. ppm 166.71, 153.50,
138.69, 136.72, 135.67, 130.36, 65.93, 52.35, 22.18, 21.49, 14.57;
HRMS (M+H) m/z, calcd for C.sub.11H.sub.14NO.sub.3, 208.0974; found
208.0981.
Example 6
Ethyl
5-methyl-3,4-dihydro-2H-pyrano[2,3-c]pyridine-6-carboxylate
##STR00033##
[0057] (a) Ethyl
2-((2-(hex-5-en-1-yloxy)-2-oxoethyl)amino)-2-oxoacetate
##STR00034##
[0059] Ethyl
2-((2-(hex-5-en-1-yloxy)-2-oxoethyl)amino)-2-oxoacetate was
prepared in a similar manner as Example 2(a) starting from
N-(t-butoxycarbonyl)glycine (2.8 g) and 5-hexen-1-ol (2.08 g).
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. ppm 7.60 (s, 1H),
5.66-5.86 (m, 1H), 4.88-5.06 (m, 2H), 4.35 (q, J=7.12 Hz, 2H), 4.17
(t, J=6.63 Hz, 2H), 4.11 (d, J=5.57 Hz, 2H), 2.06 (q, J=7.16 Hz,
2H), 1.59-1.72 (m, 2H), 1.39-1.51 (m, 2H), 1.37 (t, J=7.15 Hz, 3H);
.sup.13C NMR (75 MHz, CDCl.sub.3) .delta. ppm 168.67, 159.84,
156.57, 138.00, 114.93, 65.66, 63.25, 41.41, 33.07, 27.77, 24.91,
13.88; HRMS (M+H) m/z, calcd for C.sub.12H.sub.20NO.sub.5,
258.1341; found 258.1349.
(b) The Title Compound (A)
##STR00035##
[0061]
Ethyl-2-((2-(hex-5-en-1-yloxy)-2-oxoethyl)amino)-2-oxoacetate (0.35
g) and DCM (4 mL) were added to a vessel with stirring followed by
the addition of pyridine (0.13 g). Tf.sub.2O (0.58 g) was then
added to the mixture slowly at ambient temperature. The mixture was
stirred at ambient temperature for 4 days after which time the
mixture was extracted with 6N HCl (3.times.10 mL). The combined
acid layers were washed with DCM (10 mL) and the pH was adjusted to
.about.10 with solid K.sub.2CO.sub.3. The basic aqueous layer was
extracted with DCM (20 mL). The organic layer was concentrated
under reduced pressure to provide the title compound (A) and ethyl
2,3,4,5-tetrahydrooxepino[2,3-c]pyridine-7-carboxylate (B) as a 3:1
mixture as based on NMR analysis. .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. ppm 8.38 (s, 0.3H, cmpd B), 8.11 (s, 1H, cmpd A), 7.95 (s,
0.3H, cmpd B), 4.36-4.51 (m, 2.6H, cmpd A/B CH.sub.3CH.sub.2),
4.17-4.25 (m, 2H, cmpd A OCH.sub.2), 4.06-4.13 (m, 0.6H, cmpd B
OCH.sub.2), 2.85-2.93 (m, 0.6H, cmpd B CH.sub.2), 2.71 (t, J=6.53
Hz, 2H, cmpd A CH.sub.2), 2.45 (s, 3H, cmpd A CH.sub.3), 1.99-2.15
(m, 2.6H, cmpd A/B CH.sub.2), 1.54-1.88 (m, 0.6H, cmpd B CH.sub.2),
1.44 (t, J=7.12 Hz, 0.9H, cmpd B CH.sub.3), 1.44 (t, J=7.12 Hz, 3H,
cmpd A CH.sub.3); .sup.13C NMR (75 MHz, CDCl.sub.3) .delta. ppm
166.53, 165.01, 162.88, 159.21, 153.21, 143.48, 143.11, 142.72,
139.52, 136.74, 134.94, 130.12, 127.21, 73.82, 65.85, 61.61, 61.21,
33.74, 31.53, 24.97, 22.11, 21.48, 14.56, 14.28; Cmpd A: HRMS
(M+Na) m/z, calcd for C.sub.12H.sub.15NO.sub.3Na, 244.0950; found
244.0961; Cmpd B: HRMS (M+H) m/z, calcd for
C.sub.12H.sub.16NO.sub.3, 222.1130; found 222.1130.
Example 7
3,4-Dihydro-2H-pyrano[2,3-c]pyridine-6-carbaldehyde
##STR00036##
[0062] (a) (3,4-Dihydro-2H-pyrano[2,3-c]pyridin-6-yl)methanol
##STR00037##
[0064] To a vessel was added with stirring methyl
3,4-dihydro-2H-pyrano[2,3-c]pyridine-6-carboxylate (7.4 g, 1 eq)
and tetrahydrofuran (THF) (32 mL). The mixture was heated to
55.degree. C. whereupon 2M LiBH.sub.4 in THF solution (20 mL, 1.05
eq.) was added over 1 h. The stirring continued at 55.degree. C.
until reduction was complete at which point the mixture was cooled
to 45.degree. C. and 6N HCl (37 mL) was carefully added to the
mixture. The stirring was continued for 1 h then the mixture was
cooled to 25.degree. C. The pH was adjusted to .about.9.5 to 10
with 50 wt % aqueous NaOH solution. The organics were extracted
with 2-methyltetrahydrofuran (2.times.37 mL). The combined organic
layers were concentrated under reduced pressure and crystallized to
provide (3,4-dihydro-2H-pyrano[2,3-c]pyridin-6-yl)methanol as an
off-white solid. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. ppm 8.10
(s, 1H), 6.91-6.99 (m, 1H), 4.65 (s, 2H), 4.18-4.29 (m, 2H), 3.42
(s, 1H), 2.79 (t, J=6.50 Hz, 2H), 1.96-2.12 (m, 2H); .sup.13C NMR
(75 MHz, CDCl.sub.3) .delta. ppm 151.09, 150.39, 137.87, 131.40,
121.14, 66.51, 64.10, 24.22, 21.55; HRMS (M+H) m/z, calcd for
C.sub.9H.sub.12NO.sub.2, 166.0868; found, 166.0861.
(b) The Title Compound
[0065] (3,4-Dihydro-2H-pyrano[2,3-c]pyridin-6-yl)methanol (300 g,
1.0 eq), DCM (1.5 L) and dimethyl sulfoxide (216 mL, 2.05 eq) were
added with stirring to a vessel maintained at .about.0 to 5.degree.
C. Triethylamine (858 mL, 4.1 eq) followed by solid pyridine
sulphur trioxide (474 g, 2.0 eq) were slowly added to the mixture
while maintaining the mixture temperature at .about.0 to 7.degree.
C. The mixture was stirred at .about.0 to 7.degree. C. for .about.5
to 8 h then quenched with aqueous 5 wt % NaHCO.sub.3 solution (3 L)
to form a biphasic mixture. The layers were separated and the
aqueous layer was extracted with DCM (0.9 L). The combined organic
layers were washed with aqueous 5 wt % citric acid (3.0 L) and
brine (300 mL), dried over anhydrous sodium sulfate and filtered to
provide the title compound in DCM solution. .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. ppm 9.94 (s, 1H), 8.21-8.32 (m, 1H), 7.72 (s,
1H), 4.25-4.40 (m, 2H), 2.85 (t, J=6.50 Hz, 2H), 1.97-2.19 (m,
2H).
* * * * *